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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 6, 2006; DOI: 10.1124/jpet.105.096701

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Received for publication October 7, 2005.
Revised January 4, 2006.
Accepted for publication January 5, 2006.

Indiplon is a high-affinity positive allosteric modulator with selectivity for {alpha}1 subunit containing GABAA receptors

Robert E. Petroski 1*, Jordan E. Pomeroy 1, Ronnie Das 1, Heath Bowman 1, Weidong Yang 1, Adele P. Chen 1, Alan C. Foster 2

1 Neurocrine Biosciences 2 Neurocrine Biosciences Inc.

* Address correspondence to: E-mail: rpetroski{at}neurocrine.com

Abstract

Indiplon (NBI 34060) is a novel pyrazolopyrimidine currently in development for the treatment of insomnia. We have previously shown that indiplon exhibits high affinity binding to native GABAA receptors from rat brain and acts as a positive allosteric modulator of GABAA receptor currents in cultured rat neurons (Sullivan et al., 2004). In this study, we examined the GABAA receptor alpha subunit selectivity of indiplon using electrophysiological techniques to record GABA-activated chloride currents from recombinant rodent GABAA receptors expressed in HEK293 cells. Indiplon potentiated the GABA-activated chloride current in recombinant GABAA receptors in a dose- dependent and reversible manner and was approximately 10- fold selective for {alpha}1 subunit containing receptors over GABAA receptors containing {alpha}2, {alpha}3, or {alpha}5 subunits. The EC50 values were 2.6 nM, 24 nM, 60 nM, and 77 nM for {alpha}1{beta}2{gamma}2, {alpha}2{beta}2{gamma}2, {alpha}3{beta}3{gamma}2, and {alpha}5{beta}2{gamma}2 receptors, respectively. Indiplon was approximately 10 times more potent than zolpidem and zopiclone and > 100 times more potent than zaleplon. Moreover, indiplon, up to 1 µM did not potentiate GABAA receptors composed of {alpha}4{beta}2{gamma}2 and {alpha}6{beta}2{gamma}2 subunits. This mechanism of action is proposed to underlie the sedative-hypnotic effects of indiplon in animals and humans.


Key words: GABAA receptors, indiplon, patch clamp, zaleplon, zolpidem, zopiclone


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